It is well known in the art that the presence of sphingosine-1-phosphate receptor-1 (S1P1) is required for the transport of lymphocytes from lymphatic tissues into the peripheral circulation. However, internalization of S1P1 may prevent lymphocytes from exiting lymphatic tissues, and thus those important immunocytes will be confined in lymphatic tissues.
Many studies suggested that there exist multiple S1P1 agonists which can bind to homologous receptors expressed on lymphocytes and result in the internalization of S1P1, thereby preventing the transport of lymphocytes. S1P1 receptor agonists can reduce the ability of human to initiate immune response by preventing the transport of lymphocytes, therefore they could serve as immunosuppressants for the treatment of various autoimmune diseases.
Many S1P1 agonists have been described and the most typical compound among them is FTY720 (also known as “Fingolimod”). Now, FTY720 is promoted and sold by Novartis under a trade name “Gilenya”, for the treatment of Multiple sclerosis. Although FTY720 has clinical efficacy, it is a non-selective S1P receptor agonist and may activate several S1P receptors, such as S1P1, S1P2, S1P3, S1P4, and S1P5. The binding of FTY720 to S1P3 may result in a series of side effects, for example, bradycardia and tissue fibrosis. Therefore, many pharmaceutical companies and biotechnology groups are searching for the second generation of S1P1 agonist which is more specific and safer, so as to overcome the side effects of FTY720.
In addition to improving target specificity, shortening the in vivo half-life of drug (i.e. S1P1 receptor agonist) is another important object of screening the second generation of S1P1 agonist (Pan et al., 2013, ACS Medicinal Chemistry Letters, 4, p333). Traditionally, small molecule drugs with longer half-life are considered to be desirable, since a long half-life can avoid frequent administration of the drug. However, a long half-life may become a severe disadvantage for immunosuppressant drugs because the immunosuppressant drug may persistently inhibit the transport of lymphocytes, and thus decrease the number of lymphocytes in the peripheral blood, resulting in a reduced immune functioning and an increased risk of viral infections for drug users. The disadvantage above exists with S1P1 receptor agonist, such as FTY720, clinically used at present. In case of infection, it is often required to discontinue administration, in order to get lymphocytes in the peripheral blood return to a normal level as soon as feasible and restore the immune function of human body rapidly. As the half-life of FTY720 in the body is 6 to 9 days, a long time is needed for lymphocytes to revert to normal even after patients stop taking the medicine (Budde et al., 2002, Journal of the American Society of Nephrology, 13:1073-83).
Therefore, there is still a need for a novel S1P1 receptor agonist with high selectivity for S1P1 and a shorter half-life, to overcome deficiencies of the existing therapies.